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3
Relationship of
Macronutrients and
Physical Activity to
Chronic Disease
OVERVIEW
Over the last 40 years, a growing body of evidence has accumulated
regarding the relationships among consumption of dietary fat, carbohydrate,
protein, and energy and risk of chronic disease. The fact that diets are
usually composed of a variety of foods that include varying amounts of
carbohydrate, protein, and various fats imposes some limits on the type of
research that can be conducted to ascertain causal relationships. The avail-
able data regarding the relationships among major chronic diseases that
have been linked with consumption of dietary energy and macronutrients
(fats, carbohydrates, fiber, and protein), as well as physical inactivity, are
discussed below and are reviewed in greater detail in the specific nutrient
chapters (Chapters 5 through 11) and the chapter on physical activity
(Chapter 12).
CANCER
Diet has long been suspected as a cancer-causing agent. Early studies
in animals showed that diet could influence carcinogenesis (Tannenbaum,
1942; Tannenbaum and Silverstone, 1957). Cross-cultural studies that com-
pare incidence rates of specific cancers across populations have found
great differences in cancer incidence, and dietary factors, at least in part,
have been implicated as causes of these differences (Armstrong and Doll,
1975; Gray et al., 1979; Rose et al., 1986). In addition, observational studies
have found strong correlations among dietary components and incidence
and mortality rates of cancer (Armstrong and Doll, 1975).
53

54 DIETARY REFERENCE INTAKES
Associations among dietary fat, carbohydrates, and protein and can-
cer have been hypothesized. Many of these associations, however, have
not been supported by clinical and interventional studies in humans.
Increased intakes of energy, total fat, n-6 polyunsaturated fatty acids,
cholesterol, sugars, protein, and some amino acids have been thought to
increase the risk of various cancers, whereas intakes of n-3 fatty acids,
dietary fiber, and physical activity are thought to be protective. The major
findings and potential mechanisms for these relationships are discussed
below.
Energy
Animal studies suggest that restriction of energy intake may inhibit
cell proliferation (Zhu et al., 1999) and tumor growth (Wang et al., 2000).
A risk of mortality from cancer has been associated with increased energy
intakes during childhood (Frankel et al., 1998; Must and Lipman, 1999).
Excess energy intake is a contributing factor to obesity, which is thought to
increase the risk of certain cancers (Carroll, 1998). To support this con-
cept, a number of studies have observed a positive association between
energy intake during adulthood and risk of cancer (Andersson et al., 1996;
Lissner et al., 1992; Lyon et al., 1987), whereas other studies did not find
an association (Stemmermann et al., 1985).
Dietary Fat
High intakes of dietary fat have been implicated in the development
of certain cancers. Early cross-cultural and case-control studies reported
strong associations between total fat intake and breast cancer (Howe et al.,
1991; Miller et al., 1978; vanât Veer et al., 1990), yet a number of epidemio-
logical studies, most in the last 15 years, have found little or no association
(Hunter et al., 1996; Jones et al., 1987; Kushi et al., 1992; van den Brandt
et al., 1993; Velie et al., 2000; Willett et al., 1987, 1992). Evidence from
epidemiological studies on the relationship between fat intake and colon
cancer has been mixed as well (De Stefani et al., 1997b; Giovannucci et al.,
1994; Willett et al., 1990). Howe and colleagues (1997) reported no asso-
ciation between fat intake and risk of colorectal cancer from the com-
bined analysis of 13 case-control studies. Epidemiological studies tend to
suggest that dietary fat intake is not associated with prostate cancer (Ramon
et al., 2000; VeierÃ¸d et al., 1997b). Giovannucci and coworkers (1993),
however, reported a positive association between total fat consumption,
primarily animal fat, and risk of advanced prostate cancer. Findings on the
association between fat intake and lung cancer have been mixed (De
Stefani et al., 1997a; Goodman et al., 1988; VeierÃ¸d et al., 1997a; Wu et al.,

56 DIETARY REFERENCE INTAKES
Schatzkin et al., 2000) do not support a protective effect of dietary fiber
against colon cancer, and the issue remains to be resolved.
High-fiber diets may also be protective against the development of
colonic adenomas (Giovannucci et al., 1992; Hoff et al., 1986; Little et al.,
1993; Macquart-Moulin et al., 1987; Neugut et al., 1993). However, not all
studies have found a significant association between the dietary intake of
total, cereal, or vegetable fiber and colorectal adenomas, although a slight
reduction in risk was observed with increasing intake of fruit fiber (Platz et
al., 1997).
There are numerous hypotheses as to how fiber might protect against
the development of colon cancer. These include the dilution of carcino-
gens, procarcinogens, and tumor promoters in a bulky stool; a more rapid
rate of transit through the colon with high-fiber diets; a reduction in the
ratio of secondary bile acids to primary bile acids by acidifying colonic
contents; the production of butyrate from the fermentation of dietary fiber
by the colonic microflora; and the reduction of ammonia, which is known
to be toxic to cells (Harris and Ferguson, 1993; Jacobs, 1986; Klurfeld,
1992; Van Munster and Nagengast, 1993; Visek, 1978).
Fiber has been shown to lower serum estrogen concentrations (Rose
et al., 1991), and therefore may have a protective effect against hormone-
related cancers. Recent studies have shown a decreased risk of endome-
trial cancer (Barbone et al., 1993; Goodman et al., 1997), ovarian cancer
(Risch et al., 1994; Tzonou et al., 1993), and prostate cancer (Andersson
et al., 1996) with high fiber intakes. More research is needed before con-
clusions can be drawn on these relationships.
Although fiber has the ability to decrease blood estrogen concentra-
tions by a variety of different mechanisms (Rose et al., 1991), it is not yet
known whether this action is sufficient to decrease the risk of breast cancer.
Half of the epidemiological studies attempting to link low dietary fiber
intake to breast cancer have failed to show this relationship (Gerber, 1998).
The data on cereal intake and breast cancer risk are considerably stronger
than overall fiber intake (Rohan et al., 1993), suggesting that certain cereal
foods are protective or that only certain types and stages of breast cancer
respond to these interventions.
Physical Activity
Regular exercise, as recommended in this report, has been shown to
be negatively correlated with the risk of colon cancer (Colbert et al., 2001;
White et al., 1996). This is, in part, due to the reduction in obesity, which
is positively related to cancer (Carroll, 1998). In men and women who are
physically active, the risk of colon cancer is reduced by 30 to 40 percent
compared with those who are sedentary. A plausible mechanism for the

57
R ELATIONSHIP OF MACRONUTRIENTS AND PHYSICAL ACTIVITY
effect of physical activity on colon cancer is the shortening of intestinal
transit time, thus reducing contact time between intestinal mucosa and
carcinogens and mutagens in the diet that are carried in the fecal stream
(Batty and Thune, 2000).
Examination of more than 30 epidemiological studies concluded that
regular physical activity decreased the risk of breast cancer by 20 to 40
percent (IARC, 2002). However, relatively few studies found a consistent
association between physical activity and decreased incidence of endome-
trial cancer. For prostate cancer, results of about 20 studies were less
consistent, with only moderately strong relationships. As endogenous sex
steroids have been implicated in the development of breast, endometrial,
and prostrate cancers, a plausible explanation for the inverse relationship
among physical activity and reproductive organ cancers may involve the
effect of exercise on the binding and turnover of sex steroids and
glucoregulatory hormones, as well as the overall effect of exercise on body
fat (IARC, 2002; Vainio and Bianchini, 2001).
With regard to the possible effect of exercise on other forms of cancer,
such as pancreatic cancer (Michaud et al., 2001), exercise may also play a
beneficial role by compensating for effects of excess energy intake; by
modifying the effects of carcinogens, cocarcinogens, and cancer promoters;
or by decreasing body fat and lessening the accumulation of cancer-causing
substances in body tissues (Shephard, 1990, 1996). Regular activity may
also bolster the immune system (Bruunsgaard et al., 1999; Mazzeo et al.,
1998).
HEART DISEASE
The known risk factors for coronary heart disease (CHD) include high
serum low density lipoprotein (LDL) cholesterol concentration, low serum
high density lipoprotein (HDL) cholesterol concentration, a family history
of CHD, hypertension, diabetes mellitus, cigarette smoking, advancing age,
and obesity (Castelli, 1996; Hennekens, 1998; Parmley, 1997). There is a
positive linear relationship between serum total cholesterol and LDL
cholesterol concentrations and risk of CHD or mortality from CHD
(Jousilahti et al., 1998; Neaton and Wentworth, 1992; Sorkin et al., 1992;
Stamler et al., 1986). A low concentration of HDL cholesterol is positively
correlated with risk of CHD, independent of other risk factors (Austin et
al., 2000).
High concentrations of serum triacylglycerol may also contribute to
CHD (Austin, 1989), but the evidence is less clear. Most studies show a
positive relationship between serum triacylglycerol and CHD (Bainton et
al., 1992; Carlson and BÃ¶ttiger, 1972; Gordon et al., 1977; Hulley et al.,
1980; Stampfer et al., 1996); however, Gordon and coworkers (1977) found

58 DIETARY REFERENCE INTAKES
that the statistical significance of this relationship disappears after control-
ling for total cholesterol, LDL cholesterol, or HDL cholesterol.
The role of diet in the promotion or prevention of heart disease is the
subject of considerable research. New studies investigating dietary energy
sources and physical activity for their potential to alter some of the risk
factors for heart disease are underway (i.e., plasma cholesterol, hyper-
tension, obesity, and diabetes).
Dietary Fat
Increasing the intake of saturated fat can increase serum total choles-
terol and LDL cholesterol concentrations (Clarke et al., 1997; Hegsted et
al., 1993; Kasim et al., 1993; Krauss and Dreon, 1995; Mensink and Katan,
1992). Furthermore, a meta-analysis of 37 intervention studies showed that
a reduction in plasma total cholesterol and LDL cholesterol concentra-
tions was correlated with reductions in percentages of total dietary fat that
also included a decrease in saturated fats (Yu-Poth et al., 1999). The corre-
lation between total fat and serum cholesterol concentration is due, in
part, to the strong positive association between total fat and saturated fat
intake and the weak association between total fat and polyunsaturated fat
intake (Masironi, 1970; Stamler, 1979). Furthermore, the impact of satu-
rated fats in increasing LDL cholesterol concentration is twofold greater
than the impact of polyunsaturated fats in reducing LDL cholesterol
(Hegsted et al., 1993; Mensink and Katan, 1992). This effect, however, is
not seen with all saturated fatty acids. While lauric, myristic, and palmitic
acids increase cholesterol concentration (Mensink et al., 1994), stearic
acid has been shown to have a neutral effect (Bonanome and Grundy,
1988; Denke, 1994; Yu et al., 1995).
Similar to saturated fat, increasing intakes of trans fatty acids and
cholesterol increase serum total cholesterol and LDL cholesterol concen-
trations (Ascherio et al., 1999; Clarke et al., 1997; Hegsted, 1986; Howell
et al., 1997). Epidemiological studies have generally demonstrated a posi-
tive association between trans fatty acid intake and increased risk of heart
disease (Ascherio et al., 1994, 1996b; Hu et al., 1997; Pietinen et al., 1997;
Willett et al., 1993); however, the risk with cholesterol intake has been
mixed (Ascherio et al., 1996b; Hu et al., 1997, 1999b; Kushi et al., 1985;
Mann et al., 1997; Pietinen et al., 1997). There is wide interindividual
variation in serum cholesterol response to dietary cholesterol (Hopkins,
1992), which may be due to genetic factors.
Monounsaturated and polyunsaturated fatty acids decrease serum total
cholesterol and LDL cholesterol concentrations (Gardner and Kraemer,
1995). The epidemiological data indicate that monounsaturated fats are
either not associated or are positively associated with risk of CHD (Hu et

62 DIETARY REFERENCE INTAKES
teria in the mouth, and the presence of these sugars increases the rate and
volume of plaque formation (Depaola et al., 1999). However, because
development of caries involves other factors such as fluoride intake, oral
hygiene, food composition, and frequency of meals and snacks, sugar
intake alone is not the only cause of caries.
TYPE 2 DIABETES MELLITUS
Type 2 diabetes mellitus is characterized by a genetic predisposition to
the disorder, decreased tissue sensitivity to insulin (insulin resistance),
and impaired function of pancreatic Î²-cells, which control the timely release
of insulin (Anderson, 1999). Obesity, physical inactivity, and advancing
age are primary risk factors for insulin resistance and development of type
2 diabetes (Barrett-Connor, 1989; Colditz et al., 1990; Helmrich et al.,
1991; Manson et al., 1991). Dietary factors have also been suggested as
playing a major role in the development of insulin resistance and type 2
diabetes.
Dietary Fat
Intervention studies that have evaluated the effect of the level of fat
intake on biochemical risk factors for diabetes have been mixed (Abbott et
al., 1989; Borkman et al., 1991; Coulston et al., 1983; Fukagawa et al.,
1990; Howard et al., 1991; Jeppesen et al., 1997; Leclerc et al., 1993;
Straznicky et al., 1999; Swinburn et al., 1991; Thomsen et al., 1999; Yost et
al., 1998). Some epidemiological studies have shown a correlation between
higher fat intakes and insulin resistance (Marshall et al., 1991; Mayer-Davis
et al., 1997; Parker et al., 1993). It is not clear, however, whether the
correlation is due to fat in the diet or to obesity. Obesity, particularly
abdominal obesity, is a risk factor for type 2 diabetes (Vessby, 2000).
Decreased physical activity is also a significant predictor of higher post-
prandial insulin concentrations and may confound some studies (Feskens
et al., 1994; Parker et al., 1993).
Findings from intervention studies tend to suggest a lack of adverse
effect of saturated fat on risk indictors of diabetes in healthy individuals
(Fasching et al., 1996; Roche et al., 1998; Thomsen et al., 1999). However,
it was recently reported that the consumption of saturated fatty acids can
significantly impair insulin sensitivity (Vessby et al., 2001).
Because of the favorable effects of n-3 fatty acids (eicosapentaenoic
acid and docosahexaenoic acid) on risk indicators of coronary heart dis-
ease, they are often used in patients with lipid disorders. There has been
concern about the use of these fatty acids for lipid disorders because many
of these patients also have type 2 diabetes. A number of studies have sug-

65
R ELATIONSHIP OF MACRONUTRIENTS AND PHYSICAL ACTIVITY
Dietary Carbohydrate
A negative correlation between total sugars intake and body mass index
has been reported in adults (Dreon et al., 1988; Dunnigan et al., 1970;
Fehily et al., 1984; Gibson, 1993, 1996b; Miller et al., 1990). Increased
added sugars intakes have been shown to result in increased energy intakes
of children and adults (see Chapter 6) (Bowman, 1999; Gibson, 1996a,
1997; Lewis et al., 1992). In spite of this, a negative correlation between
added sugars intake and body mass index has been observed in children
(Bolton-Smith and Woodward, 1994; Gibson, 1996a; Lewis et al., 1992).
Published reports disagree about whether a direct link exists between the
trend toward higher intakes of sugars and increased rates of obesity. Any
association between added sugars intake and body mass index is, in all
likelihood, masked by the pervasive and serious problem of underreporting,
which is more prevalent and severe among the obese population. In addi-
tion, foods and beverages high in added sugars are more likely to be
underreported compared to other foods that may be perceived as âhealthyâ
(Johnson, 2000).
Dietary Fiber
Consumption of soluble fibers, which are low in energy, delays gastric
emptying (Roberfroid, 1993), which in turn can cause an extended feeling
of fullness and therefore satiety (Bergmann et al., 1992). A number of
intervention studies suggest that diets high in fiber may assist in weight
loss (Birketvedt et al., 2000; Eliasson et al., 1992; Rigaud et al., 1990;
RÃ¶ssner et al., 1987; Ryttig et al., 1989), although other studies have not
found this effect (Astrup et al., 1990; Baron et al., 1986). Thus, the evi-
dence to support a role of fiber in the prevention of obesity is unclear at
this time.
Physical Activity
Energy expenditure by physical activity (see Chapters 5 and 12) varies
considerably between individuals, affecting the energy balance and the
body composition by which energy balance and weight maintenance are
achieved (Ballor and Keesey, 1991; Williamson et al., 1993). Indeed, physi-
cal inactivity is a major risk factor for development of obesity in children
and adults (Astrup, 1999; Goran, 2001). In one study, increasing the level
of physical activity in obese individuals appeared to have no effect on food
intake, whereas in normal-weight individuals an increase in activity was
coupled with an increase in food intake (Pi-Sunyer and Woo, 1985).

Responding to the expansion of scientific knowledge about the roles of nutrients in human health, the Institute of Medicine has developed a new approach to establish Recommended Dietary Allowances (RDAs) and other nutrient reference values. The new title for these values Dietary Reference Intakes (DRIs), is the inclusive name being given to this new approach. These are quantitative estimates of nutrient intakes applicable to healthy individuals in the United States and Canada. This new book is part of a series of books presenting dietary reference values for the intakes of nutrients. It establishes recommendations for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids. This book presents new approaches and findings which include the following:

The establishment of Estimated Energy Requirements at four levels of energy expenditure

Recommendations for levels of physical activity to decrease risk of chronic disease

The establishment of RDAs for dietary carbohydrate and protein

The development of the definitions of Dietary Fiber, Functional Fiber, and Total Fiber

The establishment of Adequate Intakes (AI) for Total Fiber

The establishment of AIs for linolenic and a-linolenic acids

Acceptable Macronutrient Distribution Ranges as a percent of energy intake for fat, carbohydrate, linolenic and a-linolenic acids, and protein

Research recommendations for information needed to advance understanding of macronutrient requirements and the adverse effects associated with intake of higher amounts

Also detailed are recommendations for both physical activity and energy expenditure to maintain health and decrease the risk of disease.

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